In humans elevated internal temperature compromises blood pressure control culminating in reduced orthostatic tolerance (i.e., fainting) and a high probability of injury when these two stressors are combined. Our prior work has shown that the primary mechanisms responsible for these events are unrelated to baroreflex function, but rather are due to compromised control of cardiac output and cerebral perfusion. Specifically, during a hypotensive challenge while subjects are heat stressed, there is a greater reduction in cardiac output and cerebral perfusion relative to when subjects are normothermic. The precise mechanisms responsible for these events remain unknown but may be related to heat stress induced changes in: central blood volume, control of left ventricular end-diastolic volume, Frank-Starling relationship, arterial CO2 modulation of cerebral perfusion, and cerebrovascular autoregulation. Within this context, the proposed work seeks to identify the mechanisms associated with the effects of heat stress in altering the control of cardiac output and cerebral perfusion leading to compromised blood pressure control. Specific aim #1 will identify mechanisms by which cardiac output is insufficient to a hypotensive challenge while individuals are heat stressed. Specific aim #2 will examine mechanisms associated with heat stress leading to compromised cerebral perfusion during a hypotensive challenge. Specific aim #3 will investigate mechanisms responsible for large inter-subject variability with respect to the capacity to withstand a hypotensive challenge while individuals are heat stressed. These aims will be investigated by using novel techniques to address testable hypotheses that evaluate the combined effects of heat stress and hypotensive challenges on indices of central blood volume (technetium- 99m labeled red blood cells), ventricular volumes (live 3D echocardiography), central vascular pressures (direct catheterization), and cerebral perfusion (transcranial Doppler with clamping of end-tidal CO2). Data obtained from these projects will provide important mechanistic information regarding the effects of heat stress resulting in compromised blood pressure control. These data will also be valuable to those who treat individuals who have an elevated internal temperature accompanied with hemorrhagic injury. Such individuals may include soldiers fighting in conditions in which environmental temperature is elevated (e.g., Middle East), firefighters and police officers who serve in warmer climates, or individuals involved in any other incident (e.g., car accident) in which the individual is hemorrhaging combined with an elevated internal temperature. Project Narrative: Heat stress reduces the capability of individuals to control blood pressure resulting in a greater incidence of fainting when individuals are exposed to elevated environmental conditions. This project seeks to identify the mechanisms associated with altered cardiac (heart) function and control of brain blood flow that occur while individuals are heat stressed. This information will prove beneficial to those who treat individuals who have an elevated internal temperature accompanied with hemorrhagic injury (e.g., profuse bleeding), such as that which may occur in soldiers fighting in conditions in which environmental temperature is elevated (e.g., Middle East) or firefighters and police officers who serve in warmer climates. [unreadable] [unreadable] [unreadable]